Peritonitis is defined as inflammation of the peritoneum, the serosal membrane that lines the abdominal cavity and covers the organs within it. The peritoneum, which is normally sterile, reacts to various pathologic stimuli with a fairly uniform inflammatory response. Depending on the underlying pathology, the resulting peritonitis may be infectious or sterile in origin (Daley 2013).
Sterile or aseptic peritonitis may be caused by irritants such as foreign bodies, bile from a perforated gall bladder or a lacerated liver, gastric acid from a perforated ulcer or fluid from a ruptured ovarian cyst, or may result from genetically determined disorders such as polyserositis or familial Mediterranean fever and autoimmune diseases such as systemic lupus erythematosus.
Infectious peritonitis is caused by the entry of microorganisms into the abdominal cavity. It is conventionally classified into primary, secondary or tertiary peritonitis (see Holzheimer 2001).
Primary infectious peritonitis refers to spontaneous microbial invasion of the peritoneal cavity. It is often called spontaneous bacterial peritonitis. This mainly occurs in infancy and early childhood, in cirrhotic patients with ascites and immunocompromised patients.
Secondary infectious peritonitis, usually bacterial, refers to peritoneal infections secondary to intra-abdominal lesions, such as perforation of the hollow viscus, bowel necrosis, penetrating infectious processes or bacterial infection consequential to an originally aseptic peritonitis.
Peritoneal dialysis-associated peritonitis is a regrettably common, special type of secondary infectious peritonitis resulting from bacterial contamination introduced by peritoneal dialysis, an increasingly widespread treatment for end-stage renal failure.
Tertiary peritonitis is a less well-defined entity characterized by persistent or recurrent infections with organisms of low intrinsic virulence or with predisposition for the immunocompromised patient. It usually follows operative attempts to treat secondary peritonitis and is almost exclusively associated with a systemic inflammatory response.
Infectious peritonitis is often used synonymously with intra-abdominal infection or sepsis. In assessing the significance of the presence of microorganisms in the peritoneal cavity, it may be useful to distinguish between contamination (the presence of bacteria in normal sterile tissue without any host reaction), infection (the presence of bacteria in normal sterile tissue with a local inflammatory response), and sepsis (the systemic response to local infection).
A small proportion of cases of infectious peritonitis (1-5%) are caused by fungi, most commonly by Candida albicans, but also by other fungi in rare instances.
Clinically, peritonitis is often classified as either as local or diffuse. Local peritonitis refers to a site of infection, usually walled-off or contained by adjacent organs, and may also be called an intra-abdominal abscess. Diffuse peritonitis is synonymous with generalized peritonitis that spreads to the entire abdominal cavity.
The incidence of aseptic peritonitis, with its disparate causes, has not been globally assessed. The incidence of non-sporadic causes relates to the prevalence of familial Mediterranean fever and to a fraction of patients with systemic lupus erythematosus. Global figures are also lacking for primary infectious peritonitis, but this has been estimated to affect 10-30% of all patients admitted to hospital with ascites (Wiest et al 2012). The incidence of secondary peritonitis is similarly difficult to assess. Intra-abdominal infections occur in 25% of patients with multiple organ failure in surgical ICU. Peritonitis was present in 8% of all cases in a large necropsy series. Peritoneal dialysis-associated peritonitis occurs in 50-60% of patients within the first year of dialysis and recurrent episodes are common. Overall, it can be estimated that cases of secondary peritonitis, constituting by far the largest proportion of all peritonitis cases, must amount to several hundred thousand patients per year in the USA and Europe.
Granulocyte-Macrophage Colony-Stimulating Factor (GM-CSF) in Peritonitis
GM-CSF is a cytokine of the colony-stimulating factor family which is secreted by macrophages, T cells, mast cells, natural killer (NK) cells, endothelial cells and fibroblasts. It is also secreted by the peritoneal mesothelial cells, the main fixed cell component of the peritoneal membrane. Secretion from these cells may be spontaneous in culture or upregulated by Interleukin (IL)-1 (Lanfrancone et al 1992), or induced by epidermal growth factor (EGF) and tumor necrosis factor (TNF) (Demetri et al 1989). GM-CSF functions as a white blood cell growth factor, stimulating stem cells to produce granulocytes (neutrophils, eosinophils, and basophils) and monocytes. Monocytes exit the circulation and migrate into tissue, whereupon they mature into macrophages and dendritic cells. GM-CSF stimulates the proliferation and maturation of macrophages into dendritic cells, which orchestrate the responses of the surrounding neutrophils and T lymphocytes to local infectious/inflammatory processes.
In severe infections such as bacterial peritonitis, the normal immuno-inflammatory defense mechanisms involving macrophages, neutrophils and lymphocytes may not always function optimally for the patient's recovery. Volk et al (1991) described the loss of HLA-class II antigen expression and other phenotypical abnormalities of monocytes from patients with septic peritonitis and fatal outcome. These abnormalities were associated with functional defects of antigen presentation, formation of reactive oxygen species and cytokine secretion. This phenomenon was termed “immunoparalysis”, and its leading feature, the loss of HLA-DR antigen expression to <20%, was reversed by GM-CSF and interferon-gamma in vitro.
However, attempting to restore monocyte/macrophage function in bacterial peritonitis by giving systemic GM-CSF has given rise to contradictory results. Toda et al (1994) treated rats with peritonitis induced by cecal ligation and puncture with recombinant murine GM-CSF. The survival rate did not improve and animals died earlier than in the control group. Systemic GM-CSF inhibited early leukocyte sequestration in the peritoneal cavity. It was concluded that “care should be taken” in the clinical use of GM-CSF in severe infection. Similarly, Barsig et al (1996) found that prophylactic administration (by an unstated route) of murine GM-CSF neither augmented leukocyte numbers nor protected mice in a sub-lethal model of fecal peritonitis.
In contrast, Gennari et al (1994) found that subcutaneous injection of GM-CSF significantly reduced the mortality of mice that had been immunosuppressed by allogenic transfusion and subjected to cecal ligation and puncture. Macrophage and leukocyte numbers and function were not recorded. Austin et al (1995) demonstrated a prophylactic effect of intraperitoneal GM-CSF given to mice for 5 days after a traumatic injury and before inducing bacterial peritonitis by cecal ligation and puncture. This procedure improved survival, increased the yield of harvested peritoneal cells, improved aspects of peritoneal macrophage function and reduced bacterial growth indices.
In human patients with non-traumatic generalized abdominal sepsis treated with systemic antibiotics, subcutaneously administered GM-CSF reduced the rate of infectious complications and length of hospitalization (Orozco et al 2006).
Selgas et al (1996) tested the effects of intraperitoneally administered GM-CSF on the number and activation of peritoneal macrophages in peritoneal dialysis patients. There was a large increase in peritoneal macrophage numbers returning to baseline seven days after cessation of treatment. GM-CSF increased macrophage expression of CD11b/CD18 (CR3) and its counter-receptor CD54, indicating progression to a more activated state. Both the number of phagocytic cells and the phagocytic index were augmented. Peritoneal effluent cytokine-chemokine levels demonstrated an increase in IL-6 and MCP-1 levels, while TNF-alpha, IL-1, IL-8, MIP-1 alpha and RANTES were not significantly altered. GM-CSF administration did not affect the peritoneal transport of water or solutes. Minor flu-like symptoms were experienced by 2 of 8 patients (those showing the highest rise in cell numbers) on the third and last day of treatment. It was concluded that GM-CSF causes a marked and transient recruitment of primed macrophages into the peritoneum without inducing inflammatory parameters and might thus improve the peritoneal defensive capacity through potentiation of the effector functions of resident and newly recruited macrophages.
In a follow-up study, Schafer et al (1998) determined that the peritoneal macrophages were the likely source of the chemokines released upon intraperitoneal administration of GM-CSF.
Antimicrobial Treatment of Bacterial Peritonitis
Treatment of infectious peritonitis involves correction of the underlying process, such as leakage of bacteria from a bowel perforation, administration of systemic antibiotics, and supportive therapy to prevent or limit secondary complications due to organ failure (Daley 2013). Early control of the septic source is mandatory and can be achieved operatively or non-operatively.
Antimicrobial/antibiotic treatment is regarded as essential and may be applied before, during and after any surgical procedure to correct the underlying cause of infection. Antibiotic regimens with little or no activity against Gram-negative rods or anaerobic Gram-negative rods are not considered acceptable (Holzheimer 2001).
Organisms found in acute infectious peritonitis include Escherichia coli, followed by the anaerobic Bacteroides fragilis group, Gram-positive anaerobic cocci, Enterococcus spp. and Klebsiella spp. (Shinagawa et al 1994). In postoperative peritonitis, the order of frequency of organisms was found to be Enterococcus spp. followed by Pseudomonas spp., Staphylococcus spp., E. coli, Enterobacter spp. and Klebsiella spp. (8%). In a study of 100 cases of infectious peritonitis in India, Shree et al (2013) found E. coli to be the predominant aerobic pathogen, followed by Klebsiella spp., while Bacteroides fragilis was the predominant anaerobe. Fungi were only recovered in 3 cases. Approximately two-thirds of E. coli and Klebsiella spp. were extended range beta-lactamase (ESBL) positive and a high level of resistance was observed for beta lactams, ciprofloxacin, amikacin, and ertapenem. In a study of 58 patients with infectious peritonitis in Mexico, Orozco et al (2006) found the following microorganisms in descending order of frequency: E. coli, Enterococcus spp., Streptococcus spp., Klebsiella spp., Pseudomonas spp., Enterobacter spp., Staphylococcus spp., Clostridium spp., Bacteroides spp. (only 1 patient) and Candida spp. (2 patients). In peritonitis associated with peritoneal dialysis, infectious organisms reflect skin and environmental contamination of the dialysis catheter and fluid, and Staphylococcus spp. (chiefly coagulase-negative) are the most common organisms found (Troidle et al 2006).
The antibiotics recommended to treat bacterial peritonitis vary with time and place, according to the local spectrum of infections and the prevalence of antibiotic-resistant organisms, as well as the development of succeeding generations of antibiotics intended to overcome resistance. Normally a broad-spectrum bactericidal antibiotic with activity against the majority of aerobic organisms is given intravenously, together with an antibiotic active against the principal anaerobic pathogens of the B. fragilis group. Although the intraperitoneal route of giving antibiotics may be the most effective for treating generalized infectious peritonitis of whatever cause, this has not usually been done except in the treatment of peritonitis associated with peritoneal dialysis, where there is already an intraperitoneal catheter in place.